Medical Specialties Commons^™

Artificial Intelligence-Powered Assessment Of Pathologic Response To Neoadjuvant Atezolizumab In Patients With Nsclc: Results From The Lcmc3 Study, Sanja Dacic, William D Travis, Jennifer M Giltnane, Filip Kos, John Abel, Stephanie Hilz, Junya Fujimoto, Lynette Sholl, Jon Ritter, Farah Khalil, Yi Liu, Amaro Taylor-Weiner, Murray Resnick, Hui Yu, Fred R Hirsch, Paul A Bunn, David P Carbone, Valerie Rusch, David J Kwiatkowski, Bruce E Johnson, Jay M Lee, Stephanie R Hennek, Ilan Wapinski, Alan Nicholas, Ann Johnson, Katja Schulze, Mark G Kris, Ignacio I Wistuba

Faculty, Staff and Student Publications

Introduction: Pathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate.

Methods: We determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = …

Discovering Genetic Biomarkers For Targeted Cancer Therapeutics With Explainable Artificial Intelligence, Debaditya Chakraborty, Elizabeth Gutierrez-Chakraborty, Cristian Rodriguez-Aguayo, Hakan Başağaoğlu, Gabriel Lopez-Berestein, Paola Amero

Faculty, Staff and Student Publications

No abstract provided.

Survival Outcomes Of Patients With Her2/Neu-Positive Breast Cancer With Germline Brca Mutations, Fatma Nihan Akkoc Mustafayev, Mihir Amitabh Shukla, Amanda Lanier, Denái R Milton, Angelica M Gutierrez, Stephen K Gruschkus, John E Lewis, Rashmi K Murthy, Banu K Arun

Faculty, Staff and Student Publications

Background: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations.

Methods: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were …

A Novel Sik2 Inhibitor Sic-19 Exhibits Synthetic Lethality With Parp Inhibitors In Ovarian Cancer, Fang Wang, Xuejiao Yu, Jun Qian, Yumin Cao, Shunli Dong, Shenghua Zhan, Zhen Lu, Robert C Bast, Qingxia Song, Youguo Chen, Yi Zhang, Jinhua Zhou

Faculty, Staff and Student Publications

Purpose: Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer.

Methods: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, …

Safety And Tolerability Of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy, Jasmijn M Westerhoff, Lois A Daamen, John P Christodouleas, Erwin L A Blezer, Ananya Choudhury, Rosalyne L Westley, Beth A Erickson, Clifton D Fuller, Shaista Hafeez, Uulke A Van Der Heide, Martijn P W Intven, Anna M Kirby, Susan Lalondrelle, Bruce D Minsky, Stella Mook, Marlies E Nowee, Corrie A M Marijnen, Kristina M Orrling, Arjun Sahgal, Christopher J Schultz, Corinne Faivre-Finn, Robbert J H A Tersteeg, Alison C Tree, Chia-Lin Tseng, Tine Schytte, Dustin M Silk, Dave Eggert, Marco Luzzara, Jochem R N Van Der Voort Van Zyp, Helena M Verkooijen, William A Hall

Faculty, Staff and Student Publications

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy.

Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach).

Design, setting, and participants: This cohort study included adults with solid tumors treated with a …

Circulating Immune Signatures In Chronic Pancreatitis With And Without Preceding Acute Pancreatitis: A Pilot Study, Rasmus Hagn-Meincke, Dhiraj Yadav, Dana K Andersen, Santhi Swaroop Vege, Evan L Fogel, Jose Serrano, Melena D Bellin, Mark D Topazian, Darwin L Conwell, Liang Li, Stephen K Van Den Eeden, Asbjørn M Drewes, Stephen J Pandol, Chris E Forsmark, William E Fisher, Phil A Hart, Søren S Olesen, Walter G Park, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP).

Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons …

Ai-Marrvel - A Knowledge-Driven Ai System For Diagnosing Mendelian Disorders, Dongxue Mao, Chaozhong Liu, Linhua Wang, Rami Ai-Ouran, Cole Deisseroth, Sasidhar Pasupuleti, Seon Young Kim, Lucian Li, Jill A Rosenfeld, Linyan Meng, Lindsay C Burrage, Michael F Wangler, Shinya Yamamoto, Undiagnosed Diseases Network, Michael Santana, Victor Perez, Priyank Shukla, Christine M Eng, Brendan Lee, Bo Yuan, Fan Xia, Hugo J Bellen, Pengfei Liu, Zhandong Liu

Faculty, Staff and Students Publications

BACKGROUND: Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success for primary diagnosis.

METHODS: AI-MARRVEL (AIM) uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. AIM additionally incorporates expert-engineered features into training to recapitulate the intricate decision-making processes in molecular diagnosis. The online version of AIM is available at https://ai.marrvel.org. To evaluate AIM, we benchmarked it with diagnosed patients from three independent cohorts.

RESULTS: AIM …

A West African Ancestry-Associated Snp On 8q24 Predicts A Positive Biopsy In African American Men With Suspected Prostate Cancer Following Psa Screening, Jian Gu, Lisly Chery, Graciela M Nogueras González, Chad Huff, Sara Strom, Jeffrey A Jones, Donald P Griffith, Steven E Canfield, Xuemei Wang, Xuelin Huang, Pamela Roberson, Qing H Meng, Patricia Troncoso, Michael Ittmann, Michael Covinsky, Michael Scheurer, Margarita Irizarry Ramirez, Curtis A Pettaway

Faculty, Staff and Student Publications

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, …

Proton Therapy Mediates Dose Reductions To Brain Structures Associated With Cognition In Children With Medulloblastoma, Julianna Sienna, Lisa S Kahalley, Donald Mabbott, David Grosshans, Anna Theresa Santiago, Arnold Dela Cruz Paulino, Thomas E Merchant, Gohar S Manzar, Hitesh Dama, David C Hodgson, Murali Chintagumpala, Mehmet Fatih Okcu, William E Whitehead, Normand Laperriere, Vijay Ramaswamy, Ute Bartels, Uri Tabori, Julie M Bennett, Anirban Das, Tim Craig, Derek S Tsang

Faculty, Staff and Student Publications

Purpose: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy.

Methods and materials: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores.

Results: The mean dose and dose to …

Predictors And Impact Of Prolonged Vasoplegia After Continuous-Flow Left Ventricular Assist Device Implantation, Harveen K Lamba, Mary Kim, Meng Li, Andrew B Civitello, Ajith P Nair, Leo Simpson, J Patrick Herlihy, O H Frazier, Joseph G Rogers, Gabriel Loor, Kenneth K Liao, Alexis E Shafii, Subhasis Chatterjee

Faculty, Staff and Students Publications

BACKGROUND: Vasoplegia after cardiac surgery is associated with adverse outcomes. However, the clinical effects of vasoplegia and the significance of its duration after continuous-flow left ventricular assist device (CF-LVAD) implantation are less known.

OBJECTIVES: This study aimed to identify predictors of and outcomes from transient vs prolonged vasoplegia after CF-LVAD implantation.

METHODS: The study was a retrospective review of consecutive patients who underwent CF-LVAD implantation between January 1, 2005, and December 31, 2017. Vasoplegia was defined as the presence of all of the following: mean arterial pressure ≤65 mm Hg, vasopressor (epinephrine, norepinephrine, vasopressin, or dopamine) use for >6 hours …

Development Of A Weight-Band Dosing Approach For Vosoritide In Children With Achondroplasia Using A Population Pharmacokinetic Model, Yulan Qi, Ming Liang Chan, Diane R Mould, Kevin Larimore, Elena Fisheleva, Anu Cherukuri, Jonathan Day, Ravi Savarirayan, Melita Irving, Carlos A Bacino, Julie Hoover-Fong, Keiichi Ozono, Klaus Mohnike, William R Wilcox, Michael B Bober, Joshua Henshaw

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVE: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.

METHODS: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was …

Genome-Wide Association Analyses Identify 95 Risk Loci And Provide Insights Into The Neurobiology Of Post-Traumatic Stress Disorder, Caroline M Nievergelt, Adam X Maihofer, Elizabeth G Atkinson, Chia-Yen Chen, Karmel W Choi, Jonathan R I Coleman, Nikolaos P Daskalakis, Laramie E Duncan, Renato Polimanti, Cindy Aaronson, Ananda B Amstadter, Soren B Andersen, Ole A Andreassen, Paul A Arbisi, Allison E Ashley-Koch, S Bryn Austin, Esmina Avdibegoviç, Dragan Babić, Silviu-Alin Bacanu, Dewleen G Baker, Anthony Batzler, Jean C Beckham, Sintia Belangero, Corina Benjet, Carisa Bergner, Linda M Bierer, Joanna M Biernacka, Laura J Bierut, Jonathan I Bisson, Marco P Boks, Elizabeth A Bolger, Amber Brandolino, Gerome Breen, Rodrigo Affonseca Bressan, Richard A Bryant, Angela C Bustamante, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Anders D Børglum, Sigrid Børte, Leah Cahn, Joseph R Calabrese, Jose Miguel Caldas-De-Almeida, Chris Chatzinakos, Sheraz Cheema, Sean A P Clouston, Lucía Colodro-Conde, Brandon J Coombes, Carlos S Cruz-Fuentes, Anders M Dale, Shareefa Dalvie, Lea K Davis, Jürgen Deckert, Douglas L Delahanty, Michelle F Dennis, Frank Desarnaud, Christopher P Dipietro, Seth G Disner, Anna R Docherty, Katharina Domschke, Grete Dyb, Alma Džubur Kulenović, Howard J Edenberg, Alexandra Evans, Chiara Fabbri, Negar Fani, Lindsay A Farrer, Adriana Feder, Norah C Feeny, Janine D Flory, David Forbes, Carol E Franz, Sandro Galea, Melanie E Garrett, Bizu Gelaye, Joel Gelernter, Elbert Geuze, Charles F Gillespie, Slavina B Goleva, Scott D Gordon, Aferdita Goçi, Lana Ruvolo Grasser, Camila Guindalini, Magali Haas, Saskia Hagenaars, Michael A Hauser, Andrew C Heath, Sian M J Hemmings, Victor Hesselbrock, Ian B Hickie, Kelleigh Hogan, David Michael Hougaard, Hailiang Huang, Laura M Huckins, Kristian Hveem, Miro Jakovljević, Arash Javanbakht, Gregory D Jenkins, Jessica Johnson, Ian Jones, Tanja Jovanovic, Karen-Inge Karstoft, Milissa L Kaufman, James L Kennedy, Ronald C Kessler, Alaptagin Khan, Nathan A Kimbrel, Anthony P King, Nastassja Koen, Roman Kotov, Henry R Kranzler, Kristi Krebs, William S Kremen, Pei-Fen Kuan, Bruce R Lawford, Lauren A M Lebois, Kelli Lehto, Daniel F Levey, Catrin Lewis, Israel Liberzon, Sarah D Linnstaedt, Mark W Logue, Adriana Lori, Yi Lu, Benjamin J Luft, Michelle K Lupton, Jurjen J Luykx, Iouri Makotkine, Jessica L Maples-Keller, Shelby Marchese, Charles Marmar, Nicholas G Martin, Gabriela A Martínez-Levy, Kerrie Mcaloney, Alexander Mcfarlane, Katie A Mclaughlin, Samuel A Mclean, Sarah E Medland, Divya Mehta, Jacquelyn Meyers, Vasiliki Michopoulos, Elizabeth A Mikita, Lili Milani, William Milberg, Mark W Miller, Rajendra A Morey, Charles Phillip Morris, Ole Mors, Preben Bo Mortensen, Mary S Mufford, Elliot C Nelson, Merete Nordentoft, Sonya B Norman, Nicole R Nugent, Meaghan O'Donnell, Holly K Orcutt, Pedro M Pan, Matthew S Panizzon, Gita A Pathak, Edward S Peters, Alan L Peterson, Matthew Peverill, Robert H Pietrzak, Melissa A Polusny, Bernice Porjesz, Abigail Powers, Xue-Jun Qin, Andrew Ratanatharathorn, Victoria B Risbrough, Andrea L Roberts, Alex O Rothbaum, Barbara O Rothbaum, Peter Roy-Byrne, Kenneth J Ruggiero, Ariane Rung, Heiko Runz, Bart P F Rutten, Stacey Saenz De Viteri, Giovanni Abrahão Salum, Laura Sampson, Sixto E Sanchez, Marcos Santoro, Carina Seah, Soraya Seedat, Julia S Seng, Andrey Shabalin, Christina M Sheerin, Derrick Silove, Alicia K Smith, Jordan W Smoller, Scott R Sponheim, Dan J Stein, Synne Stensland, Jennifer S Stevens, Jennifer A Sumner, Martin H Teicher, Wesley K Thompson, Arun K Tiwari, Edward Trapido, Monica Uddin, Robert J Ursano, Unnur Valdimarsdóttir, Miranda Van Hooff, Eric Vermetten, Christiaan H Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Monika Waszczuk, Heike Weber, Frank R Wendt, Thomas Werge, Michelle A Williams, Douglas E Williamson, Bendik S Winsvold, Sherry Winternitz, Christiane Wolf, Erika J Wolf, Yan Xia, Ying Xiong, Rachel Yehuda, Keith A Young, Ross Mcd Young, Clement C Zai, Gwyneth C Zai, Mark Zervas, Hongyu Zhao, Lori A Zoellner, John-Anker Zwart, Terri Deroon-Cassini, Sanne J H Van Rooij, Leigh L Van Den Heuvel, Murray B Stein, Kerry J Ressler, Karestan C Koenen

Faculty, Staff and Students Publications

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), …

A Phenome-Wide Association And Mendelian Randomisation Study Of Alcohol Use Variants In A Diverse Cohort Comprising Over 3 Million Individuals, Mariela V Jennings, José Jaime Martínez-Magaña, Natasia S Courchesne-Krak, Renata B Cupertino, Laura Vilar-Ribó, Sevim B Bianchi, Alexander S Hatoum, Elizabeth G Atkinson, Paola Giusti-Rodriguez, Janitza L Montalvo-Ortiz, Joel Gelernter, María Soler Artigas, Sarah L Elson, Howard J Edenberg, Pierre Fontanillas, Abraham A Palmer, Sandra Sanchez-Roige

Faculty, Staff and Students Publications

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African …

Sialic Acid-Siglec-E Interactions Regulate The Response Of Neonatal Macrophages To Group B Streptococcus, Sean J Lund, Pamela G B Del Rosario, Asami Honda, Kaitlin J Caoili, Marten A Hoeksema, Victor Nizet, Kathryn A Patras, Lawrence S Prince

Faculty, Staff and Students Publications

The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung macrophages have lower expression levels of sialoadhesin at birth compared with the postnatal period, increasing their susceptibility to GBS infection. In this study, we investigate the mechanisms regulating sialoadhesin expression in the newborn mouse lung. In both neonatal and adult mice, GBS lung infection reduced Siglec1 expression, potentially delaying acquisition of immunity in neonates. Suppression of Siglec1 expression required interactions between sialic acid on the GBS capsule and the inhibitory host receptor Siglec-E. The Siglec1 gene contains multiple STAT binding …

Caenorhabditis Elegans Endorse Bacterial Nanocellulose Fibers As Functional Dietary Fiber Reducing Lipid Markers, Amanda Muñoz-Juan, Adrien Assié, Anna Esteve-Codina, Marta Gut, Núria Benseny-Cases, Buck S Samuel, Esther Dalfó, Anna Laromaine

Faculty, Staff and Students Publications

Bacterial nanocellulose (BNC) is a promising dietary fiber with potential as a functional food additive. We evaluated BNC fibers (BNCf) in the Caenorhabditis elegans model to obtain insight into the BNCf's biointeraction with its gastrointestinal tract while reducing the variables of higher complex animals. BNCf were uptaken and excreted by worms without crossing the intestinal barrier, confirming its biosafety regarding survival rate, reproduction, and aging for concentrations up to 34 μg/ml BNCf. However, a slight decrease in the worms' length was detected. A possible nutrient shortage or stress produced by BNCf was discarded by measuring stress and chemotactic response pathways. …

Immunotherapy Withdrawal By Step-Down To Mesalamine In Pediatric Patients With Ulcerative Colitis, Reka Szigeti, Richard Kellermayer

Faculty, Staff and Students Publications

OBJECTIVE: Parents and pediatric patients with ulcerative colitis (UC) who progressed to systemic immunotherapy are concerned about lifelong risks from such treatments. There is limited knowledge about withdrawal of such agents and step-down (SD) to enteral 5-aminosalicylic acid (mesalamine) before transitioning to adult care.

METHODS: We studied nine pediatric cases with moderate to severe UC who after a median of 2.18 years of clinical remission on systemic immunotherapy stepped down to oral mesalamine treatment.

RESULTS: Average follow-up time from SD was 3.49 years. Five patients (55.5%) had sustained remission (without any flare noted) after SD during follow-up. Sustained clinical remission …

Engineering Small-Molecule And Protein Drugs For Targeting Bone Tumors, Yixian Wang, Chenhang Wang, Meng Xia, Zeru Tian, Joseph Zhou, Julian Meyer Berger, Xiang H-F Zhang, Han Xiao

Faculty, Staff and Students Publications

Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment contributes unique signals that influence cancer growth, immunogenicity, and metastasis. Traditional cancer therapies have limited effectiveness due to off-target effects and poor distribution on bones. As a result, therapies with improved specificity and efficacy for treating bone tumors are highly needed. …

Angiogenic Gene Therapy For Refractory Angina: Results Of The Exact Phase 2 Trial, Kenta Nakamura, Timothy D Henry, Jay H Traverse, David A Latter, Nahush A Mokadam, Geoffrey A Answini, Adam R Williams, Benjamin C Sun, Christopher R Burke, Faisal G Bakaeen, Marcelo F Dicarli, Bernard R Chaitman, Mark W Peterson, Dawn G Byrnes, E Magnus Ohman, Carl J Pepine, Ronald G Crystal, Todd K Rosengart, Elaine Kowalewski, Gary G Koch, Howard C Dittrich, Thomas J Povsic, Exact Trial Investigators

Faculty, Staff and Students Publications

Background: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina.

Methods: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery.

Results: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients …

Mechanisms Driving Fasting-Induced Protection From Genotoxic Injury In The Small Intestine, Kali Deans-Fielder, Timothy Wu, Thanh Nguyen, Sarah To, Yang-Zhe Huang, Steven J Bark, Jason C Mills, Noah F Shroyer

Faculty, Staff and Students Publications

Genotoxic agents such as doxorubicin (DXR) can cause damage to the intestines that can be ameliorated by fasting. How fasting is protective and the optimal timing of fasting and refeeding remain unclear. Here, our analysis of fasting/refeeding-induced global intestinal transcriptional changes revealed metabolic shifts and implicated the cellular energetic hub mechanistic target of rapamycin complex 1 (mTORC1) in protecting from DXR-induced DNA damage. Our analysis of specific transcripts and proteins in intestinal tissue and tissue extracts showed that fasting followed by refeeding at the time of DXR administration reduced damage and caused a spike in mTORC1 activity. However, continued fasting …

Impact Of Obesity And Age On Mouse Corneal Innervation At The Epithelial-Stromal Interface, Justin A Courson, Rolando E Rumbaut, Alan R Burns

Faculty, Staff and Students Publications

PURPOSE: The corneal epithelium is the most highly innervated structure in the body. Previously, we reported a novel event whereby stromal axons fuse with basal epithelial cells, limiting nerve penetration into the epithelium. Although corneal-epithelial nerves undergo changes in sensitivity and distribution throughout life and in response to an obesogenic diet, it is unknown if neuronal-epithelial cell fusion is altered. Here, we sought to determine if neuronal-epithelial cell fusion frequency correlates with obesogenic diet consumption and age.

METHODS: Corneas were collected from C57BL/6 mice and evaluated for neuronal-epithelial cell fusion frequency using serial block-face scanning electron microscopy. To assess the …

Altered Myocardial Lipid Regulation In Junctophilin-2-Associated Familial Cardiomyopathies, Satadru K Lahiri, Feng Jin, Yue Zhou, Ann P Quick, Carlos F Kramm, Meng C Wang, Xander Ht Wehrens

Faculty, Staff and Students Publications

Myocardial lipid metabolism is critical to normal heart function, whereas altered lipid regulation has been linked to cardiac diseases including cardiomyopathies. Genetic variants in the JPH2 gene can cause hypertrophic cardiomyopathy (HCM) and, in some cases, dilated cardiomyopathy (DCM). In this study, we tested the hypothesis that JPH2 variants identified in patients with HCM and DCM, respectively, cause distinct alterations in myocardial lipid profiles. Echocardiography revealed clinically significant cardiac dysfunction in both knock-in mouse models of cardiomyopathy. Unbiased myocardial lipidomic analysis demonstrated significantly reduced levels of total unsaturated fatty acids, ceramides, and various phospholipids in both mice with HCM and …

Avoidant/Restrictive Food Intake Disorder Prevalence Is High In Children With Gastroparesis And Functional Dyspepsia, Isha Kaul, Helen Burton-Murray, Salma Musaad, Yiming Mirabile, Danita Czyzewski, Miranda A L Van Tilburg, Andrew C Sher, Bruno P Chumpitazi, Robert J Shulman

Children’s Nutrition Research Center Staff Publications

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) prevalence in children with gastroparesis (Gp) and/or functional dyspepsia (FD) is unknown. We aimed to identify ARFID prevalence and trajectory over 2 months in children with Gp, FD, and healthy children (HC) using two screening questionnaires. We also explored the frequency of a positive ARFID screen between those with/without delayed gastric emptying or abnormal fundic accommodation.

METHODS: In this prospective longitudinal study conducted at an urban tertiary care hospital, patients ages 10-17 years with Gp or FD and age- and gender-matched HC completed two validated ARFID screening tools at baseline and 2-month follow-up: the …

Genome-Wide Analysis In Over 1 Million Individuals Of European Ancestry Yields Improved Polygenic Risk Scores For Blood Pressure Traits, Jacob M Keaton, Zoha Kamali, Tian Xie, Ahmad Vaez, Ariel Williams, Slavina B Goleva, Alireza Ani, Evangelos Evangelou, Jacklyn N Hellwege, Loic Yengo, William J Young, Matthew Traylor, Ayush Giri, Zhili Zheng, Jian Zeng, Daniel I Chasman, Andrew P Morris, Mark J Caulfield, Shih-Jen Hwang, Jaspal S Kooner, David Conen, John R Attia, Alanna C Morrison, Ruth J F Loos, Kati Kristiansson, Reinhold Schmidt, Andrew A Hicks, Peter P Pramstaller, Christopher P Nelson, Nilesh J Samani, Lorenz Risch, Ulf Gyllensten, Olle Melander, Harriette Riese, James F Wilson, Harry Campbell, Stephen S Rich, Bruce M Psaty, Yingchang Lu, Jerome I Rotter, Xiuqing Guo, Kenneth M Rice, Peter Vollenweider, Johan Sundström, Claudia Langenberg, Martin D Tobin, Vilmantas Giedraitis, Jian'an Luan, Jaakko Tuomilehto, Zoltan Kutalik, Samuli Ripatti, Veikko Salomaa, Giorgia Girotto, Stella Trompet, J Wouter Jukema, Pim Van Der Harst, Paul M Ridker, Franco Giulianini, Veronique Vitart, Anuj Goel, Hugh Watkins, Sarah E Harris, Ian J Deary, Peter J Van Der Most, Albertine J Oldehinkel, Bernard D Keavney, Caroline Hayward, Archie Campbell, Michael Boehnke, Laura J Scott, Thibaud Boutin, Chrysovalanto Mamasoula, Marjo-Riitta Järvelin, Annette Peters, Christian Gieger, Edward G Lakatta, Francesco Cucca, Jennie Hui, Paul Knekt, Stefan Enroth, Martin H De Borst, Ozren Polašek, Maria Pina Concas, Eulalia Catamo, Massimiliano Cocca, Ruifang Li-Gao, Edith Hofer, Helena Schmidt, Beatrice Spedicati, Melanie Waldenberger, David P Strachan, Maris Laan, Alexander Teumer, Marcus Dörr, Vilmundur Gudnason, James P Cook, Daniela Ruggiero, Ivana Kolcic, Eric Boerwinkle, Michela Traglia, Terho Lehtimäki, Olli T Raitakari, Andrew D Johnson, Christopher Newton-Cheh, Morris J Brown, Anna F Dominiczak, Peter J Sever, Neil Poulter, John C Chambers, Roberto Elosua, David Siscovick, Tõnu Esko, Andres Metspalu, Rona J Strawbridge, Markku Laakso, Anders Hamsten, Jouke-Jan Hottenga, Eco De Geus, Andrew D Morris, Colin N A Palmer, Ilja M Nolte, Yuri Milaneschi, Jonathan Marten, Alan Wright, Eleftheria Zeggini, Joanna M M Howson, Christopher J O'Donnell, Tim Spector, Mike A Nalls, Eleanor M Simonsick, Yongmei Liu, Cornelia M Van Duijn, Adam S Butterworth, John N Danesh, Cristina Menni, Nicholas J Wareham, Kay-Tee Khaw, Yan V Sun, Peter W F Wilson, Kelly Cho, Peter M Visscher, Joshua C Denny, Million Veteran Program, Lifelines Cohort Study, Charge Consortium, Icbp Consortium, Daniel Levy, Todd L Edwards, Patricia B Munroe, Harold Snieder, Helen R Warren

Faculty, Staff and Student Publications

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Selective Transfection Of A Transferrin Receptor-Expressing Cell Line With Dna-Lipid Nanoparticles And Synthesis Of Parasite-Derived Glycans As Biomarkers For Leishmaniasis, Irodiel Vinales Lozano

Open Access Theses & Dissertations

Despite notable progress in lipid nanoparticle (LNP)-mediated gene delivery, achieving selective transfection of specific cell types, such as cancer cells, remains a significant hurdle, hindering the advancement of innovative gene therapies. In this study, we engineered an LNP formulation encapsulating plasmid DNA (pDNA) encoding the monomeric Green Lantern (mGL) fluorescent reporter protein. The DT7 peptide ligand targeting human transferrin receptor 1 (hTfR1) was also conjugated to the LNP surface for targeted delivery to hTfR1-expressing cells. Optimization of LNP composition yielded favorable particle diameter, ζ-potential, yield, and pDNA encapsulation efficiency. Evaluation of transfection selectivity using a panel of two engineered cell …

Affective Temperaments And Personality Traits In Couple Well-Being, Carmela Mento, Chiara La Barbiera, Maria Catena Silvestri, Maria Rosaria Anna Muscatello, Clemente Cedro, Antonio Bruno, Gianluca Pandolfo, Fiammetta Iannuzzo, Clara Lombardo

Journal of Mind and Medical Sciences

Background. The objective of this study is to establish the link between affective temperament traits and maladaptive personality traits, to verify whether the potential presence of elements related to emotional, affective and dysfunctional relational functioning can affect the couple satisfaction, modifying the well-being or discomfort condition. Materials and Methods. A data collection questionnaire was developed to investigate the factors associated with dysfunctional emotional, affective, and relational modes of functioning. The sample consisted of 473 subjects. Data were collected including the TEMPS-A questionnaire, The Dirty Dozen Italian Assessment and the Relationship Assessment Scale (RAS). Results. The findings of this study showed …

Phase I Trial Of Single-Photon Emission Computed Tomography-Guided Liver-Directed Radiotherapy For Patients With Low Functional Liver Volume, Enoch Chang, Franklin C L Wong, Beth A Chasen, William D Erwin, Prajnan Das, Emma B Holliday, Albert C Koong, Ethan B Ludmir, Bruce D Minsky, Sonal S Noticewala, Grace L Smith, Cullen M Taniguchi, Maria J Rodriguez, Sam Beddar, Rachael M Martin-Paulpeter, Joshua S Niedzielski, Gabriel O Sawakuchi, Emil Schueler, Luis A Perles, Lianchun Xiao, Janio Szklaruk, Peter C Park, Arvind N Dasari, Ahmed O Kaseb, Bryan K Kee, Sunyoung S Lee, Michael J Overman, Jason A Willis, Robert A Wolff, Ching-Wei D Tzeng, Jean-Nicolas Vauthey, Eugene J Koay

Faculty, Staff and Student Publications

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection.

METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were …

Pathological Response In Resectable Non-Small Cell Lung Cancer: A Systematic Literature Review And Meta-Analysis, Nathalie A Waser, Melanie Quintana, Bernd Schweikert, Jamie E Chaft, Lindsay Berry, Ahmed Adam, Lien Vo, John R Penrod, Joseph Fiore, Donald A Berry, Sarah Goring

Faculty, Staff and Student Publications

BACKGROUND: Surrogate endpoints for overall survival in patients with resectable non-small cell lung cancer receiving neoadjuvant therapy are needed to provide earlier treatment outcome indicators and accelerate drug approval. This study's main objectives were to investigate the association among pathological complete response, major pathological response, event-free survival and overall survival and to determine whether treatment effects on pathological complete response and event-free survival correlate with treatment effects on overall survival.

METHODS: A comprehensive systematic literature review was conducted to identify neoadjuvant studies in resectable non-small cell lung cancer. Analysis at the patient level using frequentist and Bayesian random effects (hazard …

Alterations In Brain Morphometric Networks And Their Relationship With Memory Dysfunction In Patients With Type 2 Diabetes Mellitus, Rye Young Kim, Yoonji Joo, Eunji Ha, Haejin Hong, Chaewon Suh, Youngeun Shim, Hyeonji Lee, Yejin Kim, Jae-Hyoung Cho, Sujung Yoon, In Kyoon Lyoo

Faculty, Staff and Student Publications

Cognitive dysfunction, a significant complication of type 2 diabetes mellitus (T2DM), can potentially manifest even from the early stages of the disease. Despite evidence of global brain atrophy and related cognitive dysfunction in early-stage T2DM patients, specific regions vulnerable to these changes have not yet been identified. The study enrolled patients with T2DM of less than five years’ duration and without chronic complications (T2DM group, n=100) and demographically similar healthy controls (control group, n=50). High-resolution T1-weighted magnetic resonance imaging data were subjected to independent component analysis to identify structurally significant components indicative of morphometric networks. Within these networks, the groups’ …

Quorum-Sensing Agr System Of Staphylococcus Aureus Primes Gene Expression For Protection From Lethal Oxidative Stress, Magdalena Podkowik, Andrew I Perault, Gregory Putzel, Andrew Pountain, Jisun Kim, Ashley L Dumont, Erin E Zwack, Robert J Ulrich, Theodora K Karagounis, Chunyi Zhou, Andreas F Haag, Julia Shenderovich, Gregory A Wasserman, Junbeom Kwon, John Chen, Anthony R Richardson, Jeffrey N Weiser, Carla R Nowosad, Desmond S Lun, Dane Parker, Alejandro Pironti, Xilin Zhao, Karl Drlica, Itai Yanai, Victor J Torres, Bo Shopsin

Faculty, Staff and Student Publications

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic …

Overexpression Of Fatty Acid Synthase Upregulates Glutamine–Fructose-6-Phosphate Transaminase 1 And O-Linked N-Acetylglucosamine Transferase To Increase O-Glcnac Protein Glycosylation And Promote Colorectal Cancer Growth, James Drury, Mariah E. Geisen, Josiane Weber Tessmann, Piotr G. Rychahou, Courtney O. Kelson

Markey Cancer Center Faculty Publications

Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro- oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine–fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro …